Development of an informatics system for accelerating biomedical research.

F1000Res. 2019;8:1430

Authors: Navale V, Ji M, Vovk O, Misquitta L, Gebremichael T, Garcia A, Fann Y, McAuliffe M

Abstract
The Biomedical Research Informatics Computing System (BRICS) was developed to support multiple disease-focused research programs. Seven service modules are integrated together to provide a collaborative and extensible web-based environment. The modules-Data Dictionary, Account Management, Query Tool, Protocol and Form Research Management System, Meta Study, Data Repository and Globally Unique Identifier -facilitate the management of research protocols, to submit, process, curate, access and store clinical, imaging, and derived genomics data within the associated data repositories. Multiple instances of BRICS are deployed to support various biomedical research communities focused on accelerating discoveries for rare diseases, Traumatic Brain Injury, Parkinson's Disease, inherited eye diseases and symptom science research. No Personally Identifiable Information is stored within the data repositories. Digital Object Identifiers are associated with the research studies. Reusability of biomedical data is enhanced by Common Data Elements (CDEs) which enable systematic collection, analysis and sharing of data. The use of CDEs with a service-oriented informatics architecture enabled the development of disease-specific repositories that support hypothesis-based biomedical research.

PMID: 32760576 [PubMed - indexed for MEDLINE]

Idiopathic left atrial appendage ostial stenosis detected by 3D transoesophageal echocardiography.

Eur Heart J Cardiovasc Imaging. 2019 Jun 01;20(6):722

Authors: Mu L, Li M, Wang Y, Ma C, Yang J

PMID: 30689787 [PubMed - indexed for MEDLINE]

An unusual cause of right ventricular outflow tract obstruction.

Eur Heart J Cardiovasc Imaging. 2019 Jun 01;20(6):657

Authors: Vô C, Carbonez K, De Beco G, Poncelet A, Moniotte S

PMID: 30689777 [PubMed - indexed for MEDLINE]

A rare case of Rosai-Dorfman disease presenting with cardiac tamponade.

Eur Heart J Cardiovasc Imaging. 2019 Jun 01;20(6):718

Authors: Tarkin JM, Wolstenholme V, Sheaff M, Westwood M, Manisty C

PMID: 30668694 [PubMed - indexed for MEDLINE]

Pre-intervention morphologic and functional echocardiographic characteristics of neonates with critical left heart obstruction: a Congenital Heart Surgeons Society (CHSS) inception cohort study.

Eur Heart J Cardiovasc Imaging. 2019 Jun 01;20(6):658-667

Authors: Slieker MG, Meza JM, Devlin PJ, Burch PT, Karamlou T, DeCampli WM, McCrindle BW, Williams WG, Morgan CT, Fleishman CE, Mertens L

Abstract
AIMS: The aims of this study were to provide a detailed descriptive analysis of pre-intervention morphologic and functional echocardiographic parameters in a large, unselected, multicentre cohort of neonates diagnosed with critical left heart obstruction and to compare echocardiographic features between the different subtypes of left-sided lesions.
METHODS AND RESULTS: Pre-intervention echocardiograms for 651 patients from 19 Congenital Heart Surgeons' Society (CHSS) institutions were reviewed in a core lab according to a standardized protocol including >150 morphologic and functional variables. The four most common subtypes of lesions were: aortic atresia (AA)/mitral atresia (MA) (29% of patients), AA/mitral stenosis (MS) (20%), aortic stenosis (AS)/MS (26%), and isolated AS (iAS) (18%). Only 17% of patients with AS/MS had an apex-forming left ventricle, compared with 0% of those with AA/MA and AA/MS (P < 0.0001). Aortic arch hypoplasia and coarctation were common across all four groups, while those with AA/MA and AA/MS had the smallest ascending aorta diameters. Flow in the ascending aorta was retrograde in 43% and 10% of the patients with AS/MS and iAS, respectively. The right ventricle was apex forming in 100% of patients with AA/MA and AA/MS, 96% with AS/MS and 70% with iAS (P < 0.0001). Moderate to severe tricuspid regurgitation was present in 13% of all patients.
CONCLUSION: This large multi-institutional study generates insight into the distribution of the functional and morphologic spectrum in patients with critical left-sided heart disease and identifies differences in these functional and morphologic characteristics between the main anatomic subtypes of critical left heart obstruction.

PMID: 30339206 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/08

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8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/07

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

10 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/10/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Eccrine Porocarcinoma: Avoiding Diagnostic Delay.

Foot Ankle Spec. 2020 Oct;13(5):415-419

Authors: Jarocki C, Kozlow J, Harms PW, Schmidt BM

Abstract
Skin cancer is the most common cancer within the United States. Reports estimate that 1 in 5 Americans will develop some form of skin cancer. Eccrine porocarcinoma is a rare type of skin cancer of sweat gland origin. Eccrine porocarcinoma is most commonly found on the lower extremities. Clinically it may appear similar to benign skin lesions and it has significant metastatic potential. The authors present a case report with 22 months' follow-up. It describes a multiyear delay in diagnosis involving 3 specialties, including primary care, dermatology, and wound physical therapy. Information is given on techniques when high-risk cutaneous cancers are suspected or encountered. A multispecialty treatment plan is discussed.Levels of Evidence: Level V.

PMID: 32924585 [PubMed - indexed for MEDLINE]

Parental health spillover effects of paediatric rare genetic conditions.

Qual Life Res. 2020 Sep;29(9):2445-2454

Authors: Wu Y, Al-Janabi H, Mallett A, Quinlan C, Scheffer IE, Howell KB, Christodoulou J, Leventer RJ, Lockhart PJ, Stark Z, Boughtwood T, Goranitis I

Abstract
PURPOSE: The complexity and severity of rare genetic conditions pose substantial burden to families. While the importance of spillovers on carers' health in resource allocation decisions is increasingly recognised, there is significant lack of empirical evidence in the context of rare diseases. The objective of this study was to estimate the health spillovers of paediatric rare genetic conditions on parents.
METHODS: Health-related quality-of-life (HRQoL) data from children with rare genetic conditions (genetic kidney diseases, mitochondrial diseases, epileptic encephalopathies, brain malformations) and their parents were collected using the CHU9D and SF-12 measures, respectively. We used two approaches to estimate parental health spillovers. To quantify the 'absolute health spillover', we matched our parent cohort to the Australian general population. To quantify the 'relative health spillover', regression models were applied using the cohort data.
RESULTS: Parents of affected children had significantly lower HRQoL compared to matched parents in the general public (- 0.06; 95% CIs - 0.08, - 0.04). Multivariable regression demonstrated a positive association between parental and child health. The mean magnitude of HRQoL loss in parents was estimated to be 33% of the HRQoL loss observed in children (95% CIs 21%, 46%).
CONCLUSION: Paediatric rare genetic conditions appear to be associated with substantial parental health spillovers. This highlights the importance of including health effects on family members and caregivers into economic evaluation of genomic technologies and personalised medicine. Overlooking spillover effects may undervalue the benefits of diagnosis and management in this context. This study also expands the knowledge of family spillover to the rare disease spectrum.

PMID: 32266555 [PubMed - indexed for MEDLINE]

Comparison of clinical phenotype with genetic and laboratory results in 31 patients with congenital dysfibrinogenemia in northern Slovakia.

Int J Hematol. 2020 Jun;111(6):795-802

Authors: Simurda T, Zolkova J, Kolkova Z, Loderer D, Dobrotova M, Skornova I, Brunclíkova M, Grendar M, Lasabova Z, Stasko J, Kubisz P

Abstract
Congenital dysfibrinogenemia (CD) is a rare disorder of hemostasis. The majority of cases are caused by heterozygous missense mutations in one of the three fibrinogen genes. Patients with CD may experience bleeding and thrombosis, but many are asymptomatic. To better describe the clinical, laboratory, and genotypic picture of CD, we evaluated 31 patients from seven unrelated families using standard coagulation tests and genetic analysis. The clinical phenotype consisted of bleeding in 13/31 (42%) patients; other patients (18/31; 58%) were asymptomatic. Among patients with bleeding, symptoms were mostly in single anatomical sites, with variable intensity of bleeding. Compared to results from a previous large systematic survey, our results showed a similar mean bleeding score, but a higher incidence of bleeding episodes without thrombotic complications. In the present study, we identified three known pathogenic point mutations in the FGA (c.95G > A, c.104G > A) and FGB (c.586C > T) genes. The variants of CD identified in this cross-sectional study were either asymptomatic or had bleeding manifestations and showed similar laboratory features, irrespective of genotype. Results from genetic and clinical studies will continue to yield valuable information on the structure and function of the fibrinogen molecule.

PMID: 32166693 [PubMed - indexed for MEDLINE]

Hemophagocytic relapsed intramedullary plasmacytoma.

Int J Hematol. 2020 Jun;111(6):888-890

Authors: Mouhieddine TH, Barlogie B, Teruya-Feldstein J

Abstract
We report a case of a relapsed hemophagocytic intramedullary plasmacytoma, previously non-phagocytic, in conjunction with development of a new clone with different cytogenetic abnormalities forming a solitary plasmacytoma.

PMID: 31900879 [PubMed - indexed for MEDLINE]

HPO2Vec+: Leveraging heterogeneous knowledge resources to enrich node embeddings for the Human Phenotype Ontology.

J Biomed Inform. 2019 08;96:103246

Authors: Shen F, Peng S, Fan Y, Wen A, Liu S, Wang Y, Wang L, Liu H

Abstract
BACKGROUND: In precision medicine, deep phenotyping is defined as the precise and comprehensive analysis of phenotypic abnormalities, aiming to acquire a better understanding of the natural history of a disease and its genotype-phenotype associations. Detecting phenotypic relevance is an important task when translating precision medicine into clinical practice, especially for patient stratification tasks based on deep phenotyping. In our previous work, we developed node embeddings for the Human Phenotype Ontology (HPO) to assist in phenotypic relevance measurement incorporating distributed semantic representations. However, the derived HPO embeddings hold only distributed representations for IS-A relationships among nodes, hampering the ability to fully explore the graph.
METHODS: In this study, we developed a framework, HPO2Vec+, to enrich the produced HPO embeddings with heterogeneous knowledge resources (i.e., DECIPHER, OMIM, and Orphanet) for detecting phenotypic relevance. Specifically, we parsed disease-phenotype associations contained in these three resources to enrich non-inheritance relationships among phenotypic nodes in the HPO. To generate node embeddings for the HPO, node2vec was applied to perform node sampling on the enriched HPO graphs based on random walk followed by feature learning over the sampled nodes to generate enriched node embeddings. Four HPO embeddings were generated based on different graph structures, which we hereafter label as HPOEmb-Original, HPOEmb-DECIPHER, HPOEmb-OMIM, and HPOEmb-Orphanet. We evaluated the derived embeddings quantitatively through an HPO link prediction task with four edge embeddings operations and six machine learning algorithms. The resulting best embeddings were then evaluated for patient stratification of 10 rare diseases using electronic health records (EHR) collected at Mayo Clinic. We assessed our framework qualitatively by visualizing phenotypic clusters and conducting a use case study on primary hyperoxaluria (PH), a rare disease, on the task of inferring relevant phenotypes given 22 annotated PH related phenotypes.
RESULTS: The quantitative link prediction task shows that HPOEmb-Orphanet achieved an optimal AUROC of 0.92 and an average precision of 0.94. In addition, HPOEmb-Orphanet achieved an optimal F1 score of 0.86. The quantitative patient similarity measurement task indicates that HPOEmb-Orphanet achieved the highest average detection rate for similar patients over 10 rare diseases and performed better than other similarity measures implemented by an existing tool, HPOSim, especially for pairwise patients with fewer shared common phenotypes. The qualitative evaluation shows that the enriched HPO embeddings are generally able to detect relationships among nodes with fine granularity and HPOEmb-Orphanet is particularly good at associating phenotypes across different disease systems. For the use case of detecting relevant phenotypic characterizations for given PH related phenotypes, HPOEmb-Orphanet outperformed the other three HPO embeddings by achieving the highest average P@5 of 0.81 and the highest P@10 of 0.79. Compared to seven conventional similarity measurements provided by HPOSim, HPOEmb-Orphanet is able to detect more relevant phenotypic pairs, especially for pairs not in inheritance relationships.
CONCLUSION: We drew the following conclusions based on the evaluation results. First, with additional non-inheritance edges, enriched HPO embeddings can detect more associations between fine granularity phenotypic nodes regardless of their topological structures in the HPO graph. Second, HPOEmb-Orphanet not only can achieve the optimal performance through link prediction and patient stratification based on phenotypic similarity, but is also able to detect relevant phenotypes closer to domain expert's judgments than other embeddings and conventional similarity measurements. Third, incorporating heterogeneous knowledge resources do not necessarily result in better performance for detecting relevant phenotypes. From a clinical perspective, in our use case study, clinical-oriented knowledge resources (e.g., Orphanet) can achieve better performance in detecting relevant phenotypic characterizations compared to biomedical-oriented knowledge resources (e.g., DECIPHER and OMIM).

PMID: 31255713 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/09/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Brain. 2020 Sep 26;:

Authors: Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M

Abstract
Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

PMID: 32979048 [PubMed - as supplied by publisher]

The peripheral T-cell lymphomas: an unusual path to cure.

Lancet Haematol. 2020 Oct;7(10):e765-e771

Authors: Ma H, Marchi E, O'Connor OA

Abstract
Over the past 30 years, the scientific community has made little progress in changing the natural history of peripheral T-cell lymphomas. Of the haematological malignancies, T-cell lymphomas have an extremely poor prognosis. One reason for this poor outcome has been that no treatment programme has ever been developed specifically for the broader category of the disease-peripheral T-cell lymphoma-let alone any of the specific subtypes, except advances made for patients with CD30-positive anaplastic large cell lymphoma. Decades of effort have focused on retrofitting chemotherapy programmes used for other diseases, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma, which have not been associated with much progress, and have universally produced far more toxicity than benefit. A remarkable heterogeneity, a paucity of cases, and the absence of peripheral T-cell lymphoma-specific drugs, until recently at least, have limited the field's ability to make substantive and innovative advances. Over the past few years, however, it appears the field is beginning to make progress. Lineage and disease-specific novel-to-novel platforms are producing, although perhaps not unsurprisingly, compelling results suggesting that the path to a cure for this rare orphan disease might be heading in a different direction.

PMID: 32976753 [PubMed - as supplied by publisher]

Research in Rare Diseases - When Less is More.

Curr Med Chem. 2020;27(29):4754-4755

Authors: Barriuso J

PMID: 32614738 [PubMed - indexed for MEDLINE]